• GPiia'
• endocam
• platelet endothelial cell adhesion molecule, PECAM-1

MAJOR LINKS FOR CD31  

• NCBI LocusLink Record: 5175
• Mendelian Inheritance in Man (OMIM): 173445
• SwissProt annotated protein record: P16284

• Primarily an adhesion molecule; no enzymatic activity known

CELLULAR FUNCTION OF CD31  

• CD31 has been demonstrated to bind in a homophilic manner (CD31 binds CD31 on the apposing cell), and and also mediates heterophilic interactions involving non-CD31 molecules. The latter may be the result of direct binding of CD31 to another molecule (although this is controversial) or the result of secondary interactions mediated by non-CD31 receptors whose activation is CD31-dependent. Homophilic binding requires domains 1 and 2*
• CD31 mediates adhesion between cells that express CD31 (endothelial cell-endothelial cell and leukocyte-endothelial cell)
• CD31 has also been shown to have signaling functions that participate in an adhesion cascade. Ligation of CD31 on leukocytes and platelets has been demonstrated to activate integrins of the beta-1 (T cells), beta-2 (T cells, NK cells, PMN, monocytes), and beta-3 families (platelets)
• mAbs to domain 6 are reported to enhance CD31 binding activity and augment platelet activation, which result in tyrosine phosphorylation of the CD31 cytoplasmic domain*

DISEASE RELEVANCE OF CD31 AND FUNCTION OF CD31 IN INTACT ANIMAL  

• CD31 has an important role in the diapedesis step of leukocyte emigration in inflammation. CD31 antibodies block neutrophil (PMN), monocyte, and NK cell diapedesis in vitro and in vivo, without affecting prior adhesion to the endothelium
• The amino terminal domains of both monocyte CD31 and endothelial cell CD31appear to be involved in homophilic interaction necessary for transendothelial migration mAbs to the membrane-proximal domains of monocyte CD31 have been reported to block migration of monocytes across the subendothelial basal lamina presumably by blocking interaction of CD31 with non-CD31 molecules and/or blocking secondary effects of CD31 on the activation of other molecules (See "CELLULAR FUNCTION OF CD31")*

• Families in which CD31 is a member
  • CD31-->immunoglobulin supergene family

MOLECULAR STRUCTURE OF CD31  

• Single chain Type I transmembrane protein
• 574 amino acid extracellular region comprised of six C2 type Ig domains, with nine consensus N-glycosylation sites
• 118 amino acid cytoplasmic tail becomes serine and tyrosine phosphorylated following cellular activation, creating docking sites for SHP-2 and perhaps other cytosolic signaling molecules*

MOLECULAR MASS OF CD31  

POST-TRANSCRIPTIONAL MODIFICATION OF CD31  

• Alternatively spliced mRNA missing exon 9 (transmembrane domain) is present in varying levels in certain cell types. The corresponding soluble protein lacking the transmembrane domain has been found in human serum*
• Additional mRNAs encoding alternatively spliced forms with various cytoplasmic tail exons missing have been found by RT-PCR in human and mouse, however proteins corresponding to these alternate forms have not yet been identified*

POST-TRANSLATIONAL MODIFICATION OF CD31  

• N-linked glycosylation accounts for about 20% of its apparent molecular size*
• Following cellular activation in different cell types, CD31 becomes phosphorylated on serine and tyrosine residues on its cytoplasmic domain*
• CD31 may also become palmitoylated on cysteine residue 595**

SUBSTRATES FOR CD31   - N/A

ENZYMES WHICH MODIFY CD31  

LIGANDS FOR CD31 AND MOLECULES ASSOCIATED WITH CD31 Link to additional info in FORUM  

• Expression limited to endothelial cells, platelets, leukocytes, and their precursors
• Expressed at high levels on all continuous endothelia; concentrated in junctions between endothelial cells in vitro
• Expressed diffusely by monocytes, neutrophils, and NK cells
• Expressed on subsets of T cells, not on circulating B cells

CD31 possesses at least 3 activities (direct participation in homophilic adhesion; participation in heterophilic adhesion, the precise mechanism(s) of which remains undefined (See "CELLULAR FUNCTION OF CD31"); and activation of integrins following CD31 cross-linking). Different CD31-bearing cells may utilize different mechanisms at different times during interactions with different cells, so observations made in one cell system may not apply to others*
• Important questions under investigation include:
• How is CD31 adhesion regulated?
• What are the downstream events that follow CD31 homophilic engagement?**
• Do alternatively spliced forms of CD31 protein exist in cells in functionally significant concentrations? If so, how do they affect the physiology of the cell?

SELECTION OF OTHER CD31-SPECIFIC REFERENCE MAB  

REVIEWS

1. DeLisser HM, Newman PJ and Albelda SM. Molecular and functional aspects of PECAM-1/CD31. Immunol. Today 1994 15:490 PubMed

2. Muller, W.A. 1995. Trends in Cardiovasc. Med. 5:15-20.

3. Newman PJ. The biology of PECAM-1. J. Clin. Invest. 1997 99:3 ** PubMed

PRIMARY CITATIONS

4. Baldwin HS, Shen HM, Yan HC, DeLisser HM, Chung A, Mickanin C, Trask T, Kirschbaum NE, Newman PJ, Albelda SM and et al. Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31): alternatively spliced, functionally distinct isoforms expressed during mammalian cardiovascular development. Development 1994 120:2539 PubMed

5. Berman ME and Muller WA. Ligation of platelet/endothelial cell adhesion molecule 1 (PECAM-1/CD31) on monocytes and neutrophils increases binding capacity of leukocyte CR3 (CD11b/CD18). J. Immunol. 1995 154:299 PubMed

6. DeLisser HM, Christofidou-Solomidou M, Strieter RM, Burdick MD, Robinson CS, Wexler RS, Kerr JS, Garlanda C, Merwin JR, Madri JA and Albelda SM. Involvement of endothelial PECAM-1/CD31 in angiogenesis. Am. J. Pathol. 1997 151:671 PubMed

7. Gumina RJ, Kirschbaum NE, Piotrowski K and Newman PJ. Characterization of the human platelet/endothelial cell adhesion molecule-1 promoter: identification of a GATA-2 binding element required for optimal transcriptional activity. Blood 1997 89:1260 ** PubMed

8. Jackson DE, Ward CM, Wang R and Newman PJ. The protein-tyrosine phosphatase SHP-2 binds platelet/endothelial cell adhesion molecule-1 (PECAM-1) and forms a distinct signaling complex during platelet aggregation. Evidence for a mechanistic link between PECAM-1- and integrin-mediated cellular signaling. J. Biol. Chem. 1997 272:6986 ** PubMed

9. Kirschbaum NE, Gumina RJ and Newman PJ. Organization of the gene for human platelet/endothelial cell adhesion molecule-1 shows alternatively spliced isoforms and a functionally complex cytoplasmic domain. Blood 1994 84:4028 PubMed

10. Liao F, Ali J, Greene T and Muller WA. Soluble domain 1 of platelet-endothelial cell adhesion molecule (PECAM) is sufficient to block transendothelial migration in vitro and in vivo. J. Exp. Med. 1997 185:1349 PubMed

11. Liao F, Huynh HK, Eiroa A, Greene T, Polizzi E and Muller WA. Migration of monocytes across endothelium and passage through extracellular matrix involve separate molecular domains of PECAM-1. J. Exp. Med. 1995 182:1337 PubMed

12. Muller WA, Ratti CM, McDonnell SL and Cohn ZA. A human endothelial cell-restricted, externally disposed plasmalemmal protein enriched in intercellular junctions. J. Exp. Med. 1989 170:399 PubMed

13. Muller WA, Weigl SA, Deng X and Phillips DM. PECAM-1 is required for transendothelial migration of leukocytes. J. Exp. Med. 1993 178:449 PubMed

14. Newman PJ, Berndt MC, Gorski J, White GC 2d, Lyman S, Paddock C and Muller WA. PECAM-1 (CD31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 1990 247:1219 PubMed

15. Newman PJ, Hillery CA, Albrecht R, Parise LV, Berndt MC, Mazurov AV, Dunlop LC, Zhang J and Rittenhouse SE. Activation-dependent changes in human platelet PECAM-1: phosphorylation, cytoskeletal association, and surface membrane redistribution. J. Cell Biol. 1992 119:239 PubMed

16. Simmons DL, Walker C, Power C and Pigott R. Molecular cloning of CD31, a putative intercellular adhesion molecule closely related to carcinoembryonic antigen. J. Exp. Med. 1990 171:2147 PubMed

17. Stockinger H, Gadd SJ, Eher R, Majdic O, Schreiber W, Kasinrerk W, Strass B, Schnabl E and Knapp W. Molecular characterization and functional analysis of the leukocyte surface protein CD31. J. Immunol. 1990 145:3889 PubMed

18. Sun QH, DeLisser HM, Zukowski MM, Paddock C, Albelda SM and Newman PJ. Individually distinct Ig homology domains in PECAM-1 regulate homophilic binding and modulate receptor affinity. J. Biol. Chem. 1996 271:11090 PubMed

19. Tanaka Y, Albelda SM, Horgan KJ, van Seventer GA, Shimizu Y, Newman W, Hallam J, Newman PJ, Buck CA and Shaw S. CD31 expressed on distinctive T cell subsets is a preferential amplifier of beta 1 integrin-mediated adhesion. J. Exp. Med. 1992 176:245 PubMed

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Portions copyright by Garland Press and by the International Workshops on Human Leukocyte Differentiation Antigens; used with permission

Modified 11/16/99   mpr@mail.nih.gov